The Overall Specific Aims of this research are to determine the mechanisms and pathogenesis of insulin resistance in the polycystic ovary syndrome (PCO). This research will provide insight into the cause(s) of PCO and of non-insulin dependent diabetes mellitus (NlDDM). PCO, a hyperandrogenic disorder of unknown etiology, is one of the most common endocrine diseases of women of reproductive age. Women with PCO are markedly insulin resistant, independent of obesity. But PCO and obesity have a synergistic deleterious effect on glucose tolerance such that 20% of obese PCO women have impaired glucose tolerance or frank NIDDM. Our preliminary epidemiologic, family, and fibroblast insulin binding studies strongly suggest that there is a genetic component to the insulin resistance of PCO. Further, there is a strikingly increased prevalence of NIDDM in families of women with PCO consistent with a causal and/or genetic association of these disorders. The Specific Aims of this proposal are: 1) To Characterize in Detail the Mechanisms of Insulin Resistance In Vivo in PCO. This will be accomplished by defining the sensitivity and responsiveness to insulin of glucose utilization and hepatic glucose production as well as the feedback inhibition of endogenous insulin secretion by insulin. The effect of gonadal steroids on these parameters will be determined by regression analysis. The sequential multiple insulin dose euglycemic glucose clamp technique will be used to define the in vivo dose-response curve to insulin and the modified frequently sampled intravenous glucose tolerance test will be used to determine C-peptide metabolism. 2) To Determine the Cellular Defects in Insulin Action in PCO. This will be accomplished by investigating in vitro insulin binding and uniformly labeled (14C)- glucose transport in isolated adipocytes. The effect of gonadal steroids on these parameters will also be assessed. 3) To Determine if Decreased Cellular Insulin Binding or Action in PCO is an Acquired or Intrinsic (? Genetic) Defect. This will be accomplished by determining whether there are persistent defects in insulin binding, insulin receptor tyrosine kinase activity, and/or glucose transport in cultured fibroblasts from PCO women.